Ullrich syndrome is a severe congenital musculoskeletal disorder affecting multiple organ systems. The major clinical features include muscle weakness, proximal joint contractures, distal hyper extensibility, kyphoscoliosis, spine rigidity and skin abnormalities. In the severe presentation of the disease, independent walking is not achieved owing to progression of muscle weakness and contractures, and most patients die of respiratory failure during the first to third decades of life. The disease has recently been shown to result from recessive or dominant negative mutations of type VI collagen genes. Collagen VI forms a filamentous network widely distributed in most soft connective tissues and cartilage. It plays important roles in cell-matrix and matrix-matrix interactions, and changes in the expression and localization of collagen VI microfibrils are associated with common musculoskeletal diseases such as osteoarthritis. This application seeks to understand the pathogenesis of Ullrich syndrome and to develop therapies for this disabling and often fatal disease. Mouse models harboring targeted collagen VI mutations will be generated and the structural organization of the extracellular matrix in tendon, joint, muscle and skin will be analyzed to delineate the pathogenic mechanisms of disease progression. The biochemical basis of collagen VI microfibrillar assembly and the effects of disrupting microfibrillar formation during musculoskeletal development will be elucidated. In addition, therapeutic approaches for Ullrich syndrome resulting from recessive and dominant negative mutations will be explored. The proposed studies will lay the groundwork for future therapeutic intervention of genetic and acquired diseases associated with disorganization of collagen VI microfibrils.